DS-437

Description

DS-437 is a dual inhibitor of protein arginine methyltransferase 5 (PRMT5) and PRMT7 (IC₅₀s = 5.9 and 6 μM, respectively). It is selective for PRMT5 and PRMT7 over a panel of 29 additional protein, DNA, and RNA methyltransferases at 50 μM, but also inhibits DNMT3A and DNMT3B (IC₅₀s = 52 and 62 μM, respectively). DS-437 (2.5 and 10 μM) inhibits symmetrical arginine dimethylation of FOXP3 in HEK293T cells, as well as symmetrical arginine dimethylation of p60 and the ribonucleoproteins SmD1/D3 and SmB/B’ in MDA-MB-231 cells in a concentration-dependent manner. It inhibits the ability of regulatory T cells (Tregs) to suppress effector T cell (Teff) proliferation in vitro in human and murine Treg suppression assays. DS-437 (10 mg/kg five times per week) reduces tumor growth in a CT26Her2 murine colon cancer model when administered in combination with the anti-p185^erbB2/neu antibody 4D5.

Uses

DS-437 has been used as an inhibitor of protein arginine methyltransferase 5 (PRMT5) to study its effect on forkhead box P3 (FOXP3) methylation and regulatory T cells (Tregs) function in 293T cells.

Biochem/physiol Actions

DS-437 is an analog of S-adenosyl methionine (SAM ), which inhibits protein arginine methyltransferases PRMT5 and PRMT7 (IC50 5.9 and 6 μM) with little interaction against a panel of 30 other human methyltransferases.